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1. 发明授权

US6132699A Microencapsulated fluorinated gases for use as imaging agents 有权
标题翻译：微胶囊化氟化气体用作成像剂
公开(公告)号：US6132699A
公开(公告)日：2000-10-17
申请号：US158295
申请日：1998-09-22
申请人： Howard Bernstein , Julie Ann Straub , Henry T. Brush , Richard E. Wing
发明人： Howard Bernstein , Julie Ann Straub , Henry T. Brush , Richard E. Wing
IPC分类号： A61K47/06 , A61B8/00 , A61K49/00 , A61K49/22 , A61B8/13
CPC分类号： A61B8/481 , A61K49/223
摘要： It has been discovered that the incorporation of fluorinated gases, especially a perfluorocarbon such as octafluoropropane, into synthetic polymeric microparticles, significantly enhances echogenicity as compared with microparticles having air incorporated therein. The microencapsulated perfluorocarbon is manufactured with a diameter suitable for the targeted tissue to be imaged, for example, for intravenous or oral administration. In one embodiment, bioadhesive microparticles are formed for enhanced imaging of mucosal surfaces.
摘要翻译：已经发现，与合并有空气的微粒相比，将氟化气体，特别是全氟化碳如八氟丙烷掺入到合成的聚合物微粒中显着增强回波反应性。制造微胶囊化全氟化碳，其直径适用于待成像的目标组织，例如用于静脉内或口服给药。在一个实施方案中，形成生物粘附微粒用于增强粘膜表面的成像。

2. 发明授权

US5853698A Method for making porous microparticles by spray drying 失效
标题翻译：通过喷雾干燥制备多孔微粒的方法
公开(公告)号：US5853698A
公开(公告)日：1998-12-29
申请号：US745676
申请日：1996-11-08
申请人： Julie Ann Straub , Edith Mathiowitz , Howard Bernstein , Henry T. Brush , Richard E. Wing
发明人： Julie Ann Straub , Edith Mathiowitz , Howard Bernstein , Henry T. Brush , Richard E. Wing
IPC分类号： A61B8/00 , A61K49/22 , A61B8/13
CPC分类号： A61B8/481 , A61K49/223
摘要： It has been discovered that the incorporation of fluorinated gases, especially a perfluorocarbon such as octafluoropropane, into synthetic polymeric microparticles, significantly enhances echogenicity as compared with microparticles having air incorporated therein. The microencapsulated perfluorocarbon is manufactured with a diameter suitable for the targeted tissue to be imaged, for example, for intravenous or oral administration. In one embodiment, bioadhesive microparticles are formed for enhanced imaging of mucosal surfaces.
摘要翻译：已经发现，与合并有空气的微粒相比，将氟化气体，特别是全氟化碳如八氟丙烷掺入到合成的聚合物微粒中显着增强回波反应性。制造微胶囊化全氟化碳，其直径适用于待成像的目标组织，例如用于静脉内或口服给药。在一个实施方案中，形成生物粘附微粒用于增强粘膜表面的成像。

3. 发明授权

US6045777A Method for enhancing the echogenicity and decreasing the attenuation of microencapsulated gases 失效
标题翻译：增强微囊化气体的回声和减少衰减的方法
公开(公告)号：US6045777A
公开(公告)日：2000-04-04
申请号：US885933
申请日：1997-06-30
申请人： Charles C. Church , Howard Bernstein , Julie Ann Straub , Henry T. Brush
发明人： Charles C. Church , Howard Bernstein , Julie Ann Straub , Henry T. Brush
IPC分类号： A61K49/00 , A61B8/00 , A61K49/22 , A61K49/04 , A61B8/14
CPC分类号： A61B8/481 , A61K49/223
摘要： It has been discovered microparticles formed from natural or synthetic polymer with thicker walls have significantly enhanced echogenicity as compared with microparticles having thinner walls. The effect of wall thickness has been determined experimentally as well as inserted into a formula for use in predicting the optimum conditions. In the preferred embodiment, the polymers are synthetic biodegradable polymers and the wall thickness is between about 100 and 660 nm, although wall thicknesses from about 20 nm to in excess of 500 nm can be used. The microparticles are manufactured with a diameter suitable for the targeted tissue to be imaged, for example, with a diameter of between 0.5 and 8 microns for intravascular administration, and a diameter of between 0.5 and 5 mm for oral administration for imaging of the gastrointestinal tract or other lumens. Preferred polymers are polyhydroxy acids such as polylactic acid-co-glycolic acid, polylactide or polyglycolide, most preferably conjugated to polyethylene glycol or other materials inhibiting uptake by the reticuloendothelial system (RES). The microspheres may be used in a variety of ultrasound imaging applications including cardiology applications, blood perfusion applications as well as for organ and peripheral vein imaging.
摘要翻译：与具有较薄壁的微粒相比，发现由具有较厚壁的天然或合成聚合物形成的微粒具有显着增强的回声性。实验确定了壁厚的影响，并将其插入到用于预测最佳条件的公式中。在优选的实施方案中，聚合物是合成的可生物降解聚合物，并且壁厚度在约100至660nm之间，尽管可以使用约20nm至超过500nm的壁厚。制造具有适于待成像的目标组织的直径的微粒，例如，用于血管内施用的直径为0.5至8微米，并且用于口服给药以用于胃肠道成像的直径为0.5至5毫米或其他流明。优选的聚合物是聚羟酸，例如聚乳酸 - 共 - 乙醇酸，聚丙交酯或聚乙交酯，最优选与聚乙二醇缀合或抑制网状内皮系统（RES）吸收的其它物质。微球可以用于各种超声成像应用，包括心脏应用，血液灌注应用以及器官和外周静脉成像。

4. 发明授权

US5837221A Polymer-lipid microencapsulated gases for use as imaging agents 失效
标题翻译：用作成像剂的聚合物 - 脂质微胶囊化气体
公开(公告)号：US5837221A
公开(公告)日：1998-11-17
申请号：US681710
申请日：1996-07-29
申请人： Howard Bernstein , Julie Ann Straub , Henry T. Brush , Charles C. Church
发明人： Howard Bernstein , Julie Ann Straub , Henry T. Brush , Charles C. Church
IPC分类号： A61K49/00 , A61K49/22 , C08J3/20 , A61K49/04 , A61K9/14
CPC分类号： A61K49/0002 , A61K49/0004 , A61K49/223
摘要： It has been discovered that the incorporation of gases, especially fluorinated gases such as perfluorocarbons, into microparticles formed from the combination of a natural or synthetic polymer and lipid have significantly enhanced echogenicity as compared with microparticles not including the lipid. Compounds other than lipids which are hydrophobic and limit the penetration and/or uptake of water into the microparticles can also be incorporated into the microparticles to enhance echogenicity. In the preferred embodiment, the polymers are synthetic biodegradable polymers. The microparticles are manufactured with a diameter suitable for the targeted tissue to be imaged, for example, with a diameter of between 0.5 and 8 microns for intravascular administration, and a diameter of between 0.5 and 5 mm for oral administration for imaging of the gastrointestinal tract or other lumens. Preferred polymers are polyhydroxy acids such as polylactic acid-co-glycolic acid, most preferably conjugated to polyethylene glycol or other materials inhibiting uptake by the reticuloendothelial system (RES). The most preferred lipids are phospholipids, preferably dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), diarachidoylphosphatidylcholine (DAPC), dibehenoylphosphatidylcholine (DBPC), ditricosanoylphosphatidylcholine, dilignoceroylphatidylcholine (DLPC), incorporated at a ratio of between 0.01-30 (w lipid/w polymer), most preferably between 0.1-10 (w lipid/w polymer). Microparticles for imaging using other detectable agents can be similarly manufactured.
摘要翻译：已经发现，与不包括脂质的微粒相比，将天然或合成聚合物和脂质的组合形成的气体，特别是氟化气体（例如全氟化碳）并入微型颗粒中显着增强了回声反应性。疏水性的脂质以外的化合物也限制在微粒中的渗透和/或吸收也可以并入微粒中以增强回声性。在优选的实施方案中，聚合物是合成的可生物降解的聚合物。制造具有适于待成像的目标组织的直径的微粒，例如直径为0.5至8微米，用于血管内施用，并且用于口服给药的直径在0.5至5mm之间以用于胃肠道成像或其他流明。优选的聚合物是聚羟基酸，例如聚乳酸 - 共 - 乙醇酸，最优选与聚乙二醇缀合或抑制网状内皮系统（RES）摄取的其它物质。最优选的脂质是磷脂，优选二棕榈酰磷脂酰胆碱（DPPC），二硬脂酰磷脂酰胆碱（DSPC），二酰氨基磷脂酰胆碱（DAPC），二苯甲酰磷脂酰胆碱（DBPC），二硫代酰基磷脂酰胆碱，二烯酰基脂肪酰胆碱（DLPC），其比例为0.01-30（w脂质/ ），最优选0.1-10（w脂/ w聚合物）。可以类似地制造用于使用其它可检测试剂成像的微粒。

5. 发明授权

US5611344A Microencapsulated fluorinated gases for use as imaging agents 失效
标题翻译：微胶囊化氟化气体用作成像剂
公开(公告)号：US5611344A
公开(公告)日：1997-03-18
申请号：US611248
申请日：1996-03-05
申请人： Howard Bernstein , Julie A. Straub , Henry T. Brush , Richard E. Wing
发明人： Howard Bernstein , Julie A. Straub , Henry T. Brush , Richard E. Wing
IPC分类号： A61B8/00 , A61K49/22
CPC分类号： A61B8/481 , A61K49/223
摘要： It has been discovered that the incorporation of fluorinated gases, especially a perfluorocarbon such as octafluoropropane, into synthetic polymeric microparticles, significantly enhances echogenicity as compared with microparticles having air incorporated therein. The microencapsulated perfluorocarbon is manufactured with a diameter suitable for the targeted tissue to be imaged, for example, for intravenous or oral administration. In one embodiment, bioadhesive microparticles are formed for enhanced imaging of mucosal surfaces.
摘要翻译：已经发现，与合并有空气的微粒相比，将氟化气体，特别是全氟化碳如八氟丙烷掺入到合成的聚合物微粒中显着增强回波反应性。制造微胶囊化全氟化碳，其直径适用于待成像的目标组织，例如用于静脉内或口服给药。在一个实施方案中，形成生物粘附微粒用于增强粘膜表面的成像。

6. 发明申请

US20100062066A1 Formulations of Tetrahydropyridine Antiplatelet Agents for Parenteral or Oral Administration 审中-公开
标题翻译：用于肠胃外或口服给药的四氢吡啶抗血小板药物的制剂
公开(公告)号：US20100062066A1
公开(公告)日：2010-03-11
申请号：US12514763
申请日：2007-11-08
申请人： Howard Bernstein , Olinda Carneiro , Rajeev A. Jain , Namrata Pandit , Shveta Rane , Julie Ann Straub
发明人： Howard Bernstein , Olinda Carneiro , Rajeev A. Jain , Namrata Pandit , Shveta Rane , Julie Ann Straub
IPC分类号： A61K9/113 , A61K31/4365
CPC分类号： A61K31/4365 , A61K9/0019 , A61K9/1075 , A61K9/1617 , A61K9/19
摘要： A pharmaceutical composition for the oral or parenteral administration of a compound of Formula (I) comprising an oil in water emulsion, wherein the oil phase comprises the free base of or a pharmaceutically acceptable salt thereof of a compound of Formula (I), and one or more surfactants which are soluble in the oil phase and/or the aqueous phase. The emulsion optionally contains one or more excipients that are soluble in the oil phase and/or the aqueous phase, such as pH modifying agents such as buffers, osmolality/tonicity modifying agents, emulsifying agents, water-soluble polymers, and preservatives. The compound of Formula (I) can be formulated as a solid material and stored until needed. Kits for forming the emulsion are provided. Prior to administration, the solid material can be reconstituted in an aqueous medium to form the emulsion.
摘要翻译：一种用于口服或肠胃外给药包含水包油乳液的式（I）化合物的药物组合物，其中所述油相包含式（I）化合物的游离碱或其药学上可接受的盐，和一种或更多的可溶于油相和/或水相的表面活性剂。乳液任选地含有一种或多种可溶于油相和/或水相的赋形剂，如pH调节剂如缓冲液，重量摩尔渗透压浓度/张力调节剂，乳化剂，水溶性聚合物和防腐剂。式（I）的化合物可以配制成固体物质并储存直至需要。提供了用于形成乳液的试剂盒。在施用前，固体材料可以在水性介质中重构以形成乳液。

7. 发明申请

US20110251562A1 RAPID DELIVERY AND/OR WITHDRAWAL OF FLUIDS 审中-公开
标题翻译：快速交付和/或取消流体
公开(公告)号：US20110251562A1
公开(公告)日：2011-10-13
申请号：US13166611
申请日：2011-06-22
申请人： Donald E. Chickering, III , Shawn Davis , Ramin Haghgooie , Howard Bernstein , Douglas A. Levinson , Mark Michelman
发明人： Donald E. Chickering, III , Shawn Davis , Ramin Haghgooie , Howard Bernstein , Douglas A. Levinson , Mark Michelman
IPC分类号： A61M5/00
CPC分类号： A61B5/6849 , A61B5/14532 , A61B5/150022 , A61B5/150099 , A61B5/150221 , A61B5/150229 , A61B5/150297 , A61B5/150389 , A61B5/150412 , A61B5/150503 , A61B5/150755 , A61B5/150969 , A61B5/150977 , A61B5/150984 , A61B5/15105 , A61B5/15113 , A61B5/15117 , A61B5/15125 , A61B5/15144 , A61B5/15186 , A61B5/157 , A61B5/685
摘要： The present invention generally relates to systems and methods for delivering and/or withdrawing a substance or substances such as blood or interstitial fluid, from subjects, e.g., from the skin and/or from beneath the skin. In one aspect, the present invention is generally directed to devices and methods for withdrawing or extracting blood from a subject, e.g., from the skin and/or from beneath the skin, using devices containing a fluid transporter (for example, one or more microneedles), and a storage chamber having an internal pressure less than atmospheric pressure prior to receiving blood. In some cases, the device may be self-contained, and in certain instances, the device can be applied to the skin, and activated to withdraw blood from the subject. The device, or a portion thereof, may then be processed to determine the blood and/or an analyte within the blood, alone or with an external apparatus. For example, blood may be withdrawn from the device, and/or the device may contain sensors or agents able to determine the blood and/or an analyte suspected of being contained in the blood. Other aspects of the present invention are directed at other devices for withdrawing blood (or other bodily fluids, e.g., interstitial fluid), kits involving such devices, methods of making such devices, methods of using such devices, and the like.
摘要翻译：本发明一般涉及用于递送和/或从皮肤和/或皮肤下方的受试者递送和/或从物质或诸如血液或间质液体中取出物质的方法。一方面，本发明一般涉及使用包含流体转运器（例如，一个或多个微针）的装置从例如皮肤和/或从皮肤下面抽取或提取血液的装置和方法）和在接收血液之前具有小于大气压的内部压力的储存室。在一些情况下，该装置可以是独立的，并且在某些情况下，可以将该装置应用于皮肤并被激活以从受试者中抽出血液。然后可以处理装置或其一部分，以单独或与外部装置一起确定血液和/或血液内的分析物。例如，血液可以从装置中取出，和/或该装置可以包含能够确定血液和/或怀疑含在血液中的分析物的传感器或试剂。本发明的其它方面涉及用于抽出血液（或其他体液，例如间质液）的其他装置，涉及这种装置的试剂盒，制造这种装置的方法，使用这种装置的方法等。

8. 发明申请

US20110129533A1 POROUS DRUG MATRICES AND METHODS OF MANUFACTURE THEREOF 有权
标题翻译：多糖药物及其制造方法
公开(公告)号：US20110129533A1
公开(公告)日：2011-06-02
申请号：US13022776
申请日：2011-02-08
申请人： Julie Straub , David Altreuter , Howard Bernstein , Donald E. Chickering, III , Sarwat Khattak , Greg Randall
发明人： Julie Straub , David Altreuter , Howard Bernstein , Donald E. Chickering, III , Sarwat Khattak , Greg Randall
IPC分类号： A61K31/337 , A61K9/10 , A61P35/00
CPC分类号： A61K9/1635 , A61K9/1611 , A61K9/1623 , A61K9/1688 , A61K9/1694
摘要： Drugs, especially low aqueous solubility drugs, are provided in a porous matrix form, preferably microparticles, which enhances dissolution of the drug in aqueous media. The drug matrices preferably are made using a process that includes (i) dissolving a drug, preferably a drug having low aqueous solubility, in a volatile solvent to form a drug solution, (ii) combining at least one pore forming agent with the drug solution to form an emulsion, suspension, or second solution and hydrophilic or hydrophobic excipients that stabilize the drug and inhibit crystallization, and (iii) removing the volatile solvent and pore forming agent from the emulsion, suspension, or second solution to yield the porous matrix of drug. Hydrophobic or hydrophilic excipients may be selected to stabilize the drug in crystalline form by inhibiting crystal growth or to stabilize the drug in amorphous form by preventing crystallization. The pore forming agent can be either a volatile liquid that is immiscible with the drug solvent or a volatile solid compound, preferably a volatile salt. In a preferred embodiment, spray drying is used to remove the solvents and the pore forming agent. The resulting porous matrix has a faster rate of dissolution following administration to a patient, as compared to non-porous matrix forms of the drug. In a preferred embodiment, microparticles of the porous drug matrix are reconstituted with an aqueous medium and administered parenterally, or processed using standard techniques into tablets or capsules for oral administration.
摘要翻译：药物，特别是低含水溶性药物以多孔基质形式提供，优选微粒，其增强药物在水性介质中的溶解。药物基质优选使用以下方法制备，所述方法包括（i）将挥发性溶剂中的药物（优选为低溶解度的药物）溶解以形成药物溶液，（ii）将至少一种成孔剂与药物溶液以形成稳定药物并抑制结晶的乳液，悬浮液或第二溶液和亲水或疏水赋形剂，和（iii）从乳液，悬浮液或第二溶液中除去挥发性溶剂和成孔剂以产生多孔基质药物。可以选择疏水性或亲水性赋形剂，以通过抑制晶体生长来稳定药物的结晶形式，或者通过防止结晶来稳定药物的无定形形式。成孔剂可以是与药物溶剂或挥发性固体化合物，优选挥发性盐不混溶的挥发性液体。在优选的实施方案中，使用喷雾干燥来除去溶剂和成孔剂。与药物的无孔基质形式相比，得到的多孔基质在给予患者后具有更快的溶解速率。在优选的实施方案中，多孔药物基质的微粒用水性介质重新配制，并肠胃外给药，或使用标准技术加工成用于口服给药的片剂或胶囊。

9. 发明申请

US20100330703A1 ASSAYS INVOLVING COLORIMETRIC AND OTHER SIGNALING 审中-公开
标题翻译：涉及彩色和其他信号的测定
公开(公告)号：US20100330703A1
公开(公告)日：2010-12-30
申请号：US12822393
申请日：2010-06-24
申请人： Howard Bernstein , Donald E. Chickering, III , Timothy M. Blicharz
发明人： Howard Bernstein , Donald E. Chickering, III , Timothy M. Blicharz
IPC分类号： G01N33/543 , G01N21/00 , G01N21/62
CPC分类号： G01N33/54313 , G01N21/78 , G01N21/783 , G01N21/80 , G01N21/82 , G01N2021/7783 , G01N2021/7786
摘要： The present invention generally relates to particles and, in particular, to methods of determining binding involving particles, e.g., using colorimetric and other signaling techniques. In one aspect, a mixture of particles of different colors (e.g., at least a first color and a second color) is provided that exhibits a first collective color, e.g., due to the presence of the different colors of particles within the mixture. The mixture can then be exposed to a medium containing a binding partner able to preferentially bind to some of the particles, e.g., particles of a first color relative to particles of a second color. The bound particles can be separated in some fashion (e.g., filtration, gravity, magnetism, centrifugal separation, etc.), such that the mixture exhibits a second collective color, e.g., due to the presence of a greater number of particles of the second color relative to the number of particles of the first color. Accordingly, by visualizing or otherwise determining a color change, a binding event may be determined. Other aspects of the invention relate to kits involving such particles, methods of promoting the making or use of such particles, or the like.
摘要翻译：本发明一般涉及颗粒，特别是关于确定涉及颗粒的结合的方法，例如使用比色和其它信号传导技术。在一个方面，提供了不同颜色（例如，至少第一颜色和第二颜色）的颗粒的混合物，其表现出第一集合颜色，例如由于在混合物内存在不同颜色的颗粒。然后可以将混合物暴露于含有能够优先结合一些颗粒的结合配偶体的介质，例如相对于第二种颜色的颗粒的第一种颜色的颗粒。结合的颗粒可以以某种方式分离（例如，过滤，重力，磁性，离心分离等），使得混合物呈现第二集合颜色，例如由于存在更多数量的第二颜色相对于第一种颜色的颗粒数。因此，通过可视化或以其他方式确定颜色变化，可以确定结合事件。本发明的其它方面涉及涉及这种颗粒的试剂盒，促进制造或使用这种颗粒的方法等。

10. 发明申请

US20070178166A1 PROCESSES FOR MAKING PARTICLE-BASED PHARMACEUTICAL FORMULATIONS FOR PULMONARY OR NASAL ADMINISTRATION 审中-公开
标题翻译：制备基于粒子的药物制剂用于肺癌或鼻咽管理的方法
公开(公告)号：US20070178166A1
公开(公告)日：2007-08-02
申请号：US11610814
申请日：2006-12-14
申请人： Howard Bernstein , Shaina Brito , Donald Chickering , Eric Huang , Rajeev Jain , Julie Straub
发明人： Howard Bernstein , Shaina Brito , Donald Chickering , Eric Huang , Rajeev Jain , Julie Straub
IPC分类号： A61K9/14
CPC分类号： A61K9/0075 , A61K9/0043 , A61K9/0073 , A61K9/143 , A61K9/145
摘要： Dry powder pharmaceutical formulations for pulmonary or nasal administration are made to provide an improved respired dose. These formulations may be blends of milled blends and may include a phospholipid, alone or in combination with other excipient materials. In one case, the process includes the steps of (a) providing particles which comprise a pharmaceutical agent, (b) blending the particles with particles of at least one first excipient to form a first powder blend; (c) milling the first powder blend to form a milled blend which comprises microparticles or nanoparticles of the pharmaceutical agent; and (d) blending the milled blend with particles of a second excipient to form a blended dry powder blend pharmaceutical formulation suitable for pulmonary or nasal administration.
摘要翻译：制备用于肺或鼻给药的干粉药物制剂以提供改善的呼吸剂量。这些制剂可以是研磨的共混物的混合物，并且可以包括单独或与其它赋形剂材料组合的磷脂。在一种情况下，该方法包括以下步骤：（a）提供包含药剂的颗粒，（b）将颗粒与至少一种第一赋形剂的颗粒混合以形成第一粉末混合物; （c）研磨第一粉末混合物以形成包含药剂的微粒或纳米颗粒的研磨混合物; 和（d）将研磨的共混物与第二赋形剂的颗粒混合以形成适于肺或鼻施用的混合的干粉混合药物制剂。

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